Submissions for variant NM_001110792.2(MECP2):c.1111T>C (p.Ser371Pro)

gnomAD frequency: 0.00005  dbSNP: rs61752371

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000132846	SCV000247926	likely benign	not specified	2013-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000132846	SCV000513569	benign	not specified	2015-08-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000470986	SCV000556753	likely benign	Severe neonatal-onset encephalopathy with microcephaly	2025-02-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000132846	SCV000919620	likely benign	not specified	2017-12-05	criteria provided, single submitter	clinical testing	Variant summary: The MECP2 c.1075T>C (p.Ser359Pro) variant involves the alteration of a non-conserved nucleotide, changing a small, polar amino acid (S) to a medium, hydrophobic residue (P). 2/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). S359 has been shown to be phosphorylated in human skin fibroblasts, and phosphorylation of MECP2 has been shown to modulate its binding affinity, gene expression, and cellular adaptations to stimuli and neuronal plasticity (Bellini_2014). However, the functional impact of replacing S359 with a proline residue has not been studied. S359 is located within the C-terminal domain, whereas most classic RTT-causing mutations lie within the methyl-CpG-binding (MBD) or transcriptional-repression (TRD) functional domains (Bienvenu_ 2002). This variant was found in 17/198183 control chromosomes at a frequency of 0.0000858, which is approximately 10 times the estimated maximal expected allele frequency of a pathogenic MECP2 variant (0.0000083), suggesting this variant is likely a benign polymorphism. This variant has been cited in both patients and controls. A family co-segregation study showed that the variant was found in the healthy mother, healthy maternal aunt, and 3 healthy cousins (1 male and 2 females) of an intellectually disabled male (Moncla_2002), suggesting that S359P is not a pathogenic variant regardless of its potential functional impact. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as likely benign.
Ambry Genetics	RCV002415625	SCV002718719	likely benign	Inborn genetic diseases	2018-05-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Centre for Population Genomics, CPG	RCV003990972	SCV004808980	benign	Rett syndrome	2024-03-13	criteria provided, single submitter	curation	This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 3.0 (BA1).
RettBASE	RCV000132846	SCV000187825	benign	not specified	2008-01-21	no assertion criteria provided	curation
PreventionGenetics, part of Exact Sciences	RCV004532590	SCV004708616	likely benign	MECP2-related disorder	2022-09-07	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).